All about genetics

Many traits in plants and animals are heritable (can be passed down
from one generation to the next), and genetics is the study of
these heritable factors. Specific conditions and rare syndromes may
have a genetic basis. Where this is the case, there will be a
variety of causes. For example, the causes may include a single
abnormal gene, a chromosomal abnormality or a genetic
predisposition, meaning a person has a higher chance compared with
the general population, to have a particular disease or
condition.

This section is written for the non-specialist individual. We
shall concentrate on two forms of inheritance, the single abnormal
gene which is changed, or 'mutated', and chromosomal
abnormalities.

The human body is made up of billions of cells. At the centre of
each cell is a special compartment called the nucleus, which stores
threads of deoxyribonucleic acid (DNA). These threads are wrapped
in structures called chromosomes. Chromosomes are composed of
around 50,000 genes. Genes are composed of small stretches of DNA
and are our body's genetic 'blue print', giving important
instructions to build all the different molecules our bodies need
to carry out important chemical reactions and processes that keep
us alive. Genes are also responsible for determining normal traits
such as blood groups or hair colour, as well as causing disease
when the genes are damaged or mutated.

Apart from the sex cells: the ovum (the 'egg' from the female)
and the sperm (from the male), every cell in the human body
normally contains 23 pairs of chromosomes (46 in total). This
number of chromosomes is known as the 'diploid' number. Of the 23
pairs of chromosomes in each cell, one pair is from the mother and
one from the father. The first 22 of our pairs of chromosomes are
called autosomal chromosomes. The chromosomes in the twenty-third
pair are called the sex chromosomes (X and Y), named because they
determine the sex of an individual. Males have an X and Y
chromosome, while females have two X chromosomes.

The chromosomes in our sex cells undergo a special process of
division, known as meiosis so that they contain 23 'single' human
chromosomes (instead of 23 pairs). This 'half number' of
chromosomes is known as the 'haploid' number. In this way, the
mother contributes half the genetic material and the father
contributes half of the genetic material of a child.

When a baby is conceived, one ovum and one sperm fuse together.
Upon fertilisation, there are a total of 23 pairs of chromosomes,
making 46 chromosomes in total. Inheritance will depend upon the
arrangement of the genes on our chromosomes and the way in which
genes act when they are passed down through generations.

Visiting a genetics centre...got questions about it?

We talked to Adam Shaw, Consultant in Clinical Genetics at Guy's
Hospital and he answered common questions that parents have when
visiting a genetic service. We've split this into three short
podcasts

An abnormal or mutated gene may be considered as a variant of a
'normal' gene because it is changed in some way and therefore does
not give out the instruction that it should do. This change may
occur spontaneously by chance and have no significance for the
individual concerned.

In other cases, a gene that mutates (changes its character) may
give rise to specific inherited disorders where there is no
previous family history. Inheritance of the mutated gene may be
autosomal dominant, autosomal recessive or X-linked recessive (see
Types of inheritance).

Research has shown that, in many conditions, there may be
different types of mutation in a single gene, all of which can
result in the same clinical outcome. For example, in cystic
fibrosis over two hundred different mutations can occur in the
implicated gene, but they mostly produce the same disease pattern
and symptoms in individuals with cystic fibrosis.

Types of inheritance

Autosomal inheritance means that males or females are equally
affected, this is because the mutation is not passed on the sex
chromosomes (the X or Y chromosomes) and, therefore, there is not a
higher chance of either a male or female receiving the
mutation.

Autosomal dominant inheritance

Some conditions are caused by a mutation in a gene that is
dominant. As a person receives two copies of every gene (one from
the mother and one from the father), the dominant mutated gene
overrides the normal gene and the individual will be affected by
that genetic condition. In dominant inheritance, the chance of
passing on the disorder is 50 per cent for each pregnancy, (as
illustrated in the diagram below).

In some cases, there is some variability in the expression of
the dominant gene, which is known as 'penetrance'. Penetrance is
not complete in some individuals, resulting in a milder form of the
condition rather than the full effect usually seen when inheriting
the dominant gene.

Sometimes a condition with autosomal dominant inheritance may
arise due to a mutation in ovum or sperm that joined to make a
baby. When this happens and the parent of the child is not affected
(there is no preceding history), the process is known as a
'sporadic' mutation. Sporadic mutations can arise for a number of
reasons, but are usually caused by an error in copying the genetic
material. It is unlikely for parents to have another child affected
by the same sporadic mutation. The occurrence of a sporadic
mutation is unlikely to be as a result of anything the parents have
or have not done.

Autosomal recessive inheritance

In this form of inheritance, the affected gene is recessive.
This means that a person must inherit two copies of the mutated
gene, one copy from each parent, to be affected by the disorder. If
a person inherits just one copy of a mutated gene and one normal
copy then, in most cases, the person will not be affected by the
condition but is a healthy 'carrier'. Being a carrier means that a
person does not have the condition but carries a mutated copy of
the gene, which can be passed on to future generations.

Each child of parents that both carry the same mutated gene
therefore has a 25 per cent chance of inheriting a mutated gene
from both parents and, therefore, being affected by the condition.
This chance remains the same for all pregnancies and is the same
for males and females.

There is also a 50 per cent chance that the child will inherit
just one mutated copy of the gene from a parent. In this case the
child will be a healthy carrier like their parent.

Unless the parents are related, the chances of marrying a
carrier with the same mutated recessive gene are low. The incidence
of recessive genes in the population varies with different
conditions. A number of testing options may be available for people
who have a family history of a recessive genetic condition and this
information may be useful when planning pregnancies. Genetic
counselling or advice should be sought if there is a family history
of a recessive genetic condition.

X-linked inheritance

As discussed earlier, one pair of chromosomes determines a
person's sex, with a female having two X chromosomes and a male
having one X and one Y chromosome. Females inherit one X chromosome
from their father and one X chromosome from their mother, whereas
males inherit an X chromosome from their mother and their Y
chromosome from their father. The X chromosome has many genes,
whereas the Y chromosome is smaller and contains fewer genes.
Sometimes a mutation occurs on the X chromosome and genetic
conditions that occur as a result of this kind of mutation are
known as X-linked genetic conditions.

X-linked recessive inheritance

This is a recessive form of inheritance where the mother carries
the mutated gene on the X chromosome. As females have two copies of
the X chromosome, if there is a mutated gene on one of their copies
the normal copy on the other X chromosome compensates for the
mutated gene. In this case, the female is usually unaffected by the
condition and is a carrier. As a male only has one copy of the X
chromosome, if this has a mutated gene they will be affected with
the condition that this causes. In some cases, females may display
mild symptoms of the condition. An example of this is Fragile X
Syndrome. Usually though the female is less affected than male
counterparts.

If a female carrier of an X-linked recessive condition has a
daughter, she will pass on either the X chromosome with the normal
gene or the X chromosome with the mutated gene. Each daughter of a
female carrier, therefore, has a 50 per cent chance of inheriting
the mutated gene and being a carrier like their mother. If the
daughter does not inherit the mutated gene, she is not a
carrier.

If a male with an X-linked condition has a daughter, he will
always pass on one copy of the mutated gene to his daughters and
they will be carriers. This is because males only have one X
chromosome.

If a male with an X-linked condition has a son, then his son
will never inherit the mutated gene on the X chromosome. This is
because men always pass their Y chromosome to their sons.

X-lined dominant inheritance

Very rarely, X-linked conditions are passed on in a dominant
way, one such example is Coffin-Lowry syndrome. This means
that even though a female inherits one normal copy of the gene and
one mutated copy, she will have the condition as the dominant
mutated gene overrides the normal copy. If a male inherits a
mutated gene on the X chromosome then he will have the condition,
as he will only have one copy of the X chromosome.

An affected female will have a 50 per cent chance of passing the
disorder on to both her sons and her daughters. An affected male
will pass the condition on to all his daughters, but not to his
sons.

Mitochondrial inheritance

The DNA in a cell is largely located in the nucleus of the cell,
but in the surrounding cytoplasm (jelly-like material that holds
together cell components) of the cell there are small bodies called
mitochondria, which are responsible for energy production.
Mitochondria carry their own genes and DNA. These genes can also be
passed on during reproduction. However, the pattern of inheritance
is not always predictable since there is a chance element in
determining the amount of cytoplasm and hence the amount of
mitochondrial DNA that is passed on.

Mitochondrial DNA is passed on through the egg but not by the
sperm as it is only the nucleus of the sperm that enters the egg
during fertilisation. Therefore, the pattern we see with
mitochondrial inheritance is transmission through an affected
female to a variable number of male and female offspring, but no
transmission from an affected male.

Imprinted genes

In most cases, it will not matter whether the gene or chromosome
defect is inherited from the mother or father - the effect on the
child will be the same. However, there are some mutations in genes
and chromosome in which there will be a different effect depending
on which parent the abnormality has come from. For example, a
deletion of chromosome 15 from the father in the sperm will cause
Prader-Willi syndrome, whereas
the same deletion of chromosome 15 from the mother in the ovum
(egg) will cause a different condition called Angelman
syndrome.

With these imprinted genes, it is necessary to have both the
maternal (that of the mother) and paternal (that of the father)
contribution in early embryonic development in the womb. It is
likely that the need for a contribution from both parents has
arisen in evolutionary terms with sexual reproduction.

Chromosomal abnormalities

A chromosome is a rod-like structure present in the nucleus of
all cells within the body, with the exception of the red blood
cells. A chromosome has a centromere in the centre from which the
arms radiate. The q arms are long arms and the p arms are the short
arms.

A chromosomal change or abnormality occurs when there is a
defect in a chromosome or in the arrangement of the genetic
material on the chromosome. Chromosomal abnormalities give rise to
specific physical features, but it should be stressed that there
may be wide variations in the severity of the symptoms in
individuals with the same chromosome abnormality.

Additional material may be attached to a chromosome, absence of
a whole or part of a chromosome may occur and defective formation
of the chromosome may also occur. Increases and decreases in
chromosomal material, and therefore genes, interfere with normal
body function and development.

There are two main types of chromosomal abnormality that may
occur during meiosis (specialised sex cell division) and
fertilisation. These are known as numerical aberrations (changes in
the number of chromosomes from the norm) and structural aberrations
(where the normal structure of a chromosome has changed).

Numerical aberrations

Sometimes there is a failure in chromosome division (meiosis) in
the ovum and sperm before they fuse and there maybe extra or fewer
chromosomes. This can result in anomalies such as Down's syndrome
(47 chromosomes, with three copies of chromosome 21) or Turner
syndrome (45 chromosomes where the second X chromosome in
females is missing or abnormal). The following are examples of
numerical aberrations:

triploidy - this is where a cell has one extra set of
chromosomes, so there are 69 chromosomes instead of 46

mosaicism - this is where only some of the body's cells carry
an extra set of chromosomes

trisomy - this is where one extra complete chromosome is
present, so the number of chromosomes in each affected cell would
be 47 instead of 46

monosomy - this is when a complete chromosome is missing and
the number of chromosomes in a cell is 45 instead of 46.

Structural aberrations

These occur where there is a rearrangement in the location of,
or a loss of, genetic material. They occur because of breakages in
a chromosome, which can either be 'de novo' occurring
spontaneously, or be inherited from a parent. Structural disorders
include the following:

insertion - this occurs when a segment in one chromosome
inserts into a gap in another chromosome

deletion - this involves a loss of a part or segment of a
chromosome. Very small deletions are known as microdeletions

duplication - this occurs when an extra copy of a segment of a
chromosome is present. These are sometimes known as partial
trisomy. If a person has two extra copies of a chromosomal segment,
then this is known as a triplication or a partial tetrasomy. Very
small duplications are known as microduplications

inversions - this occurs when there are two breaks in a single
chromosome. The segment between break points rotates 180° and
reinserts itself back into the gap created by the original
breaks

ring formations - this occurs when the ends of both arms of the
same chromosome are deleted and the remaining broken ends become
'sticky' and join together to make a ring shape, in these cases it
is the deleted DNA that is significant. Sometimes ring chromosomes
are extra chromosomes and in which case it is the extra material
that is significant and causes symptoms in a person

reciprocal translocation (balanced, unbalanced and
Robertsonian) - this occurs when DNA is transferred from one
non-homologous (as in not in a pair with the other chromosome of
the same number) chromosome to another. In a balanced
translocation, there are breaks in two or more chromosomes and the
resulting DNA fragments swap places. If genetic material is lost
then the translocation is known as 'unbalanced'. Robertsonian
translocations occur when the short arms of chromosomes 13, 14, 15,
21 or 22 are lost and the remaining long arms fuse together.

Identifying disease-causing genes

Karotyping

This is the analysis of chromosomes under a light microscope.
The test can be performed on almost any tissue, including amniotic
fluid (fluid taken in an amniocentesis test), blood and bone
marrow. Chromosomes are stained and then photographed to show the
arrangement of the chromosomes. Certain abnormalities can be
identified through the number or arrangement of the chromosomes.
These can include large deletions and extra chromosomes.

Fluorescent in Situ Hybridisation (FISH)

In Fluorescent in Situ Hybridisation (FISH) known segments of
DNA (called probes) are fluorescently labelled and used to analyse
chromosomes. The probes are mixed with samples from the person
being tested containing their chromosomes, often taken from blood
samples, and bind to small parts of a chromosome. Once bound with
the chromosomes the probes mark them with fluorescent colours,
which can be visualised under a fluorescent microscope. If a probe
for an area of DNA which is known to cause a genetic condition if
deleted is not present on FISH, it can be assumed that this area of
DNA is missing. FISH is useful if the chromosome suspected to have
a change in it is known. For an information leaflet visit Unique.

Microarray comparative hybridisation
(array-CGH)

This is a new technique and allows identification of small
changes in genetic material that it may not be possible to identify
with karotyping. Unlike FISH the chromosome on which the change is
suspected to be on does not need to be known and a person's whole
genome (all their DNA) can be checked for changes that may cause a
genetic condition.

This technique compares reference DNA to that of the patient,
allowing the test to distinguish differences between the two sets
of DNA. In this way, deletions or duplications and the affected
genes can be identified. The patient and reference DNA are labelled
with different colour fluorescent dyes and attached to a special
glass slide called a microarray. The DNA is allowed to bind
together sticking to sequences that match exactly and the
fluorescence emitted is measured. If there is a lot more
fluorescence from the reference DNA compared with the patient's DNA
for one probe, this means that some DNA is missing in the patient
(eg deletion) and vice versa. For an information leaflet on this
test visit Unique.

Descriptions of particular chromosomal formations are often
written in a shortened form. This indicates the total number of
chromosomes, the sex of the individual and the abnormal chromosome
number.

For example, a girl with Cri du Chat syndrome would be
shortened to 46,XX,5p - that is, the affected child has 46
chromosomes, is a female (XX) and has a deletion (indicated by the
minus sign) of the short arm of chromosome 5 (which is named the p
arm). If this chromosome was in the form of a ring it would be
46,XX,r(5), the 'r' standing for ring. A trisomy could be written
as 47,XY, + 21, for a male with Down's syndrome, indicating an
additional copy of chromosome 21.

Genetic pre-disposition in multifactorial
disorders

Conditions such as isolated malformations or common diseases
like diabetes or heart disease combine a genetic pre-disposition to
develop a disease with other environmental factors that may also
contribute. There may be an undefined family history of the
condition. Where two affected children are born in the same family,
there may be an increased risk of recurrence. An example of a
condition which falls into this category is cleft lip
and/or palate.

Genetic counselling

Genetic counselling can usually calculate risks of parents
having a child affected by a genetic condition. It can also provide
support and advice for families who already have an affected child
and wish to enlarge their family. A list of regional genetics
centres are provided by the
Genetic Alliance UK.

There are a number of techniques that are used to diagnose
conditions in unborn babies whose mothers are at risk of having a
baby with an abnormality. Risks may include a family history of an
abnormality, or that the parents have already had one child with,
for example, a heart defect. On the other hand, prenatal testing
may be performed on the grounds of the age of the mother. Some
tests are offered to all mothers as part of the
NHS Fetal Anomaly Screening Programme, see their website for
more details

Ultrasound scanning

This technique involves the use of ultrasonic waves (sound waves
of a high frequency which cannot be heard by the human ear) to scan
the unborn baby (fetus) and measure it. The fetus can be seen on a
computer screen attached to the scanner enabling bone problems and
other abnormalities to be identified. Fetal measurements taken at
the scan can be compared with average 'normal' fetal age
measurements to identify abnormalities.

Amniocentesis

The amniotic sac is the bag of fluid in which the baby floats in
the womb. Amniocentesis is a way of removing some of this fluid for
further analysis by passing a fine needle through the abdomen
(belly area) into the womb. The sample of fluid is then analysed
and certain biochemical, chromosomal or neural tube defects can be
identified. Amniocentesis can identify metabolic diseases (where
the affected enzyme has been previously identified) and chromosome
defects; is usually offered at around 14 weeks of pregnancy. There
is a very small chance (around 0.5 per cent) of miscarriage after
amniocentesis.

Chorionic villus sampling

After fertilisation of the ovum by the sperm, a cell mass is
formed. The inner cells of this mass form the fetus, while the
outer cells become embedded in the wall of womb forming the
placenta (a connection between the mother and baby through which
oxygen and nutrients pass). These placenta cells are called chorion
cells and can be removed for analysis in a test called chorionic
villus sampling or (CVS).

The cells are removed using a fine needle that passes through
the abdominal wall and aspirating (drawing) some tissue back into a
syringe. This test can be performed at 11 to 13 weeks and can
identify metabolic defects where the affected enzyme has been
isolated, chromosomal defects and certain single gene defects where
the specific gene has previously been identified. There is a very
small chance (around one per cent) of miscarriage after CVS.

Related information

Further information on genetics, patterns of inheritance and
chromosome disorders can be found by accessing the following
resources.